I thought I was in Paris, so much French was being spoken. The conversations in the cafes, on the streets, in the subways – everywhere – were in French. It turns out that with its 4,000,000 plus residents, Montreal is the second largest French speaking city in the world. I couldn’t understand a word anyone was saying but the beauty of the language was evident. (Thankfully, they quickly switch to English when needed.)

My Parisian Uber driver told me, however, that Canadian French is not correct French at all – it is, he sniffed, anglicized French which he had trouble understanding at first. French, he assured me, is the easiest language to learn because, in contrast to English, it actually has rules that it follows. Plus, in French you actually say all the letters. He demonstrated that by pronouncing Toronto the way it should be pronounced (Tor-on-To) and then the way he said Torontonians pronounce it (Tor-an-do). (A Torontonian informs me the pronunciation is more like “tronno”). He also informed me, that because the French were first on the green and gentle isle that is England, English is actually French spoken poorly. ????

The conference took place in auditoriums in a French hospital – the CHU Sainte-Justine (there are French and English hospitals in Montreal) – home to one of the four most important pediatric centers in North America. The auditoriums, which tended to be packed (Ron Davis’s talk was standing room only), were a step up from the usual hotel conference room. Having the conference off-site from the hotel, on the other hand, required some extra work and expense. The food, which was generous, included the most interesting hors d’oeuvres I’ve ever seen. The only real miss was the “rest room” which consisted of a very small room with a pad on the floor and a chair.

The CHU Sainte-Justine is one of four important pediatric centers in North America.

Canada has recovered nicely from the weird rejection a couple of years ago of all grant applications for federally funded research studies on the grounds that chronic fatigue syndrome (ME/CFS) is not a real disease. The conference was funded by the second grant, plus Canadian and U.S. groups (Solve ME/CFS Initiative, Open Medicine Foundation). Plus, Canada is going to fund a small research center that will collaborate with the NIH-funded research centers in the U.S.

The conference came about from a few key actions. Christian Godbout, a Montreal patient who was too ill to attend but whose father was present (and regularly attends ME/CFS conferences), pressed an influential doctor to get Montreal to do more. The doctor got in touch with the best researcher he knew of – Alain Moreau – and asked him to produce an overview of ME/CFS research with the idea of identifying research needs.

As Moreau worked his way through the overview, he became intrigued with the disease and applied for both the first, rejected grant, as well as the grant which helped pay for the conference. The NIH funding of the ME/CFS centers prompted Canada to provide funds towards a small research center that will collaborate with the U.S. ones. Plus, I was told Canadian officials have promised to be more proactive about getting the word out about ME/CFS.

This is just to show that individuals can make a difference and that you never know the impact your actions may end up having.

As with every conference, the talks were a jumble of snoozers, moderately exciting ones and positively scintillating ones. Alain Moreau and his counterparts did a good job highlighting Canadian researchers and doctors while bringing in some excellent outside researchers.

It was particularly good to see Carmen Scheibenbogen show up. Scheibenbogen, a German researcher with her fingers in many pies, was there attending her first (but hopefully not her last) North American ME/CFS conference. Roland Staud, one of the rare researchers to cross over from fibromyalgia to ME/CFS, made, I believe, his first appearance at an ME/CFS conference as well. I missed several presentations but Maureen Hanson, Betsy Keller and Nancy Klimas provided particularly thought-provoking presentations.

Maureen Hanson – The One Problem to Rule Them All?

Hanson headed off the Metabolic section, and as she did so, she noted Canada’s excellent, free Human Metabolite Database (HMDB) which contains detailed information about 114,100 metabolites. It wasn’t a groundbreaking new study result that made Maureen Hanson’s talk so interesting: it was her conclusions.

Hanson – known to be a rigorous researcher – has been comparing the results of past metabolome studies to see if the results match up. Are we getting more or less consistent results or are the results all over the map?

Could metabolism be ground zero for chronic fatigue syndrome (ME/CFS?)

Whether we’re getting consistent results or getting a jumble of results from metabolomics studies is a very important question given the amount of interest and effort that has gone into the field recently. Ian Lipkin is adding metabolomic studies to his portfolio. After finding some darn interesting cytokine findings, the Simmaron Research Foundation is exploring the metabolomics of spinal fluid.

I still go back to Ron Davis’s findings with his son; after doing test after test after test, it was only the metabolomics results that impressed him. This field needs to replicate those results, though, for them to be considered solid.

It wasn’t looking good early on as Hanson noted the different platforms used, the different sample types used (serum vs plasma), the different extraction methods, the different ways samples were stored, etc. All these possible confounding factors in a rather finicky field seemed to presage disaster, but in the end the news was good. Except for the studies which used plasma vs. serum, the findings were actually very consistent, and even in the plasma vs. serum studies, the numbers weren’t that far off.

As to the applicability of metabolomics to ME/CFS, Hanson reported she was able to identify 95% of ME/CFS patients correctly using 41 metabolites. Her search for metabolomic subsets failed – suggesting perhaps that metabolic problems are at the core of ME/CFS; that they may be THE central driver which gives rise to the subsets that are probably found in ME/CFS.

Hanson perhaps gave a clue to what she thinks is going on when she noted the 2014 Vermoulen study which suggested low oxygen flow to the tissues was causing the problems with exercise in ME/CFS.

Hanson is currently doing or will do a two-day metabolomic and exercise study, which I believe is part of her NIH research center grant. If ME/CFS is indeed a hypometabolic state that’s held in place by problems with energy production, the results of the two-day exercise study will be fascinating. Will that hypometabolic state – always measured during rest so far – get even more hypometabolic after the two-day exercise trials? This is the kind of big, complex and expensive study that we need the NIH for.

Betsy Keller – The Ever-Evolving Exercise Picture in ME/CFS

Keller first thanked the Workwell Foundation for getting her into this field. Most of the patients she sees are there for disability evaluations.

Quite a few groups are doing exercise studies, but it’s the Workwell Foundation – composed of exercise physiologists – which has contributed the most eye-opening finding of all: that the ability of ME/CFS patients to generate energy gets whacked by exercise. That finding is all too obvious to anyone with ME/CFS, but it turns out that that finding may be unique to ME/CFS.

Keller stated that people with lung disease, heart disease or sedentary controls are able to replicate their energy production to a surprisingly precise degree (differing by 1-7%) on the second day of a two-day maximal exercise test. Many people with ME/CFS cannot – something happens to them during or after exercise to disturb one of the most fundamental biological processes of all: their ability to turn oxygen into energy goes down, sometimes quite severely. Hanson reported that a former marathon runner’s ability to produce energy went down a staggering 44% after one maximal exercise test.

Ventilation is proving to be a major issue in ME/CFS. (By John Pierce [CC0], from Wikimedia Commons).

As more research is slowly, slowly being done, the field has evolved. VO2 max and anaerobic threshold were the central foci early on but it’s becoming clear that the exercise issues in ME/CFS are more complicated than that.

The ventilatory response – the breathing we do to remove the CO2 waste products and get more oxygen to our tissues – is often deranged in ME/CFS as well. If you can’t remove the excess CO2 produced during exercise, you’re going to be in pain fairly quickly. (Of my two single exercise tests done years ago, my ventilatory response was the only measure that was off — and it was way off.) Dr. Systrom has said that breathing problems during exercise are almost universally found in ME/CFS.

The heart rate should increase at a certain rate during exercise in order to propel more blood to the tissues. It’s becoming clear that a problem called chronotropic incompetence – or, the inability to properly increase the heart rate during exercise – is common in ME/CFS.

After exercise, the heart rate should drop at a certain rate as the person recovers. Within six minutes, their systolic blood pressure should come down to resting levels. Each of these can also be off in ME/CFS.

One might expect a lot of lactate production in aerobically challenged ME/CFS patients, but sometimes Hanson sees little lactate production. (Lactate – a toxin – is a function of anaerobic energy production). This odd situation is probably occurring not because the patients aren’t energetically impaired but because they’re so lousy at producing energy anaerobically. Their tests, Dr. Hanson said, are over very quickly – too quickly to produce a lot of lactate. Ventilation is a better measure in these patients.

Dr. Keller has a paper in review. It’s great to see Dr. Keller digging deeper into this oh-so-fundamental problem in ME/CFS.

Cara Tomas – from Julia Newton’s group in the U.K – noted some of the different results we’re getting in mitochondrial studies. Every study is finding something wrong, but at times, quite different things wrong. As Maureen Hanson did, Cara went over some of the possible confounding factors.

She used the Seahorse machine in the Newton group’s latest study – that machine, at least, shows some consistency. The Seahorse is currently being used in several studies (Hanson, Barao, Newton). She was surprised to find that mitochondrial function was not worse in the severely ill ME/CFS patients, when compared to moderately ill patients. That finding, which needs to be replicated, could suggest that factors other than the ability to produce energy are needed to produce more severe ME/CFS.

Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results. Tomas first assessed the ability of ME/CFS patients’ and healthy controls’ immune cells to create energy in low and high glucose concentrations. Adding glucose should boost up glycolysis – the anaerobic portion of the energy cycle – and it did – but only in the healthy controls. The inability of the ME/CFS patients’ cells to utilize the extra glucose seemed to suggest that something had gone wrong with glycolysis in ME/CFS, but then came a twist: a glycolysis stress test indicated that glycolysis was operating normally.

The ME/CFS patients’ immune cells couldn’t generate nearly as much energy as the healthy controls.

As Tomas went through her tests and found that ME/CFS patients’ immune cells underperformed in every situation she put them in, suggesting they were stuck in a kind of low energy mode. When given extra glucose, they weren’t able to use it. When deprived of glucose, they weren’t able to increase their mitochondrial energy production.

The fact that ME/CFS patients’ cells had lower reserve capacity suggested they may have already been operating near their maximum level. The low coupling efficiency suggested that, when pushed, they simply didn’t have the resources to respond. When asked to respond, the ME/CFS cells were able to generate only about a quarter of the energy of the healthy controls.

The study was on immune cells, not muscle cells, but each finding seemed to make sense given ME/CFS patients’ inability to mount the energy to engage in exercise.

The healthy controls’ cells, on the other hand, demonstrated the flexibility and adaptability healthy cells need to have to respond to the different situations they will inevitably face.

All in all, it was a remarkable set of findings which made several of the Ramsay Award studies the SMCI has funded of double interest. A couple of years ago, the SMCI made investigating the energy production of immune cells a top priority. Ramsay award winner Chris Armstrong is studying the metabolism of B-cells under a variety of conditions. Isabel Barao is using the Seahorse machine to see if problems with energy production are hampering NK cells’ notorious problems killing other cells in ME/CFS, and Brupesh Prusty is determining if HHV-6 infections are hampering mitochondrial functioning in ME/CFS. Those studies should be finished or finishing up soon.

In fact, Ramsay Award winners were on full display at this conference: they included Carmen Scheibenbogen (2 Ramsay studies), Jonas Bergquist, Chris Armstrong and Maureen Hanson.

Roland Staud – Fatigue and the ME/CFS Brain

Staud was an inspired choice as he’s one of the very few researchers to study both ME/CFS and FM – and we could dearly use researchers who have a foot in both worlds. This is the first time, I believe, that he’s shown up at an ME/CFS conference.

A rheumatologist based in Florida, Staud has for many years focused entirely on FM and pain, but in the last three years, this well-published researcher has produced no less than six studies on ME/CFS.

Bad Brain Motor?

Could the brain not be activating the muscles in ME/CFS properly?

Staud stated that his recent brain imaging study used a different, more precise kind of brain imaging called spin labeling which provides better imaging of neuronal functioning. His goal was to see whether blood flow to the brain overall was reduced, and whether blood flow to brain areas that are associated with fatigue is altered in ME/CFS. Since blood flow is an indirect measure of energy – the brain directs more blood to areas of it that are active – the study measured blood flow during a fatiguing cognitive task.

Staud found that, in contrast to some studies, there were no differences in overall blood flow to the brains of people with ME/CFS, but found a paradoxical result when brain blood flow was looked at in more detail. Increased blood flow to parts of the brain associated with memory and cognition (superior temporal gyri (STG), precuneus, and fusiform gyrus) were associated with decreased fatigue in healthy controls but increased fatigue in the ME/CFS patients during the cognitive task and afterwards.

In other words, blood flow to one part of the brain produced exactly opposite fatigue responses in the ME/CFS patients vs. the healthy controls. Patients with the greatest reductions in blood flow to one part of the brain (precuneus, left fusiform gyrus) after the cognitive task experienced the least fatigue. These parts of the brain are believed to affect attention, motor coordination, and sense of self/self-reflection.

That suggests that some sort of flip has occurred in ME/CFS and the fatigue reduction pathways are now responsible for producing fatigue in ME/CFS – a bizarre finding, but then again bizarre findings are not unusual in ME/CFS.

A currently embargoed paper by Staud is expanding on his findings. It found altered “connectivity” i.e. transmission between the precuneus and portions of the brain associated with movement planning and motor function (supplementary motor area, precentral gyrus, basal ganglia), cognitive control (superior frontal gyrus), and sensory function (thalamus) both during resting state and during cognitive tests.

Notice the possible issues with movement planning and “motor functioning” (movement) Staud is finding. He’s not the first – others in the rather distant past uncovered possible issues with engaging the muscles in ME/CFS, but the research mostly lapsed. Miller’s basal ganglia studies of a couple of years ago underlined possible problems with “motor functioning” in ME/CFS. Now Staud is adding to that oh-so-interesting theme. If the brain is not engaging the muscles properly – they should be sequentially engaged as the need arises – then fatigue is an inevitable result.

A big question is why decreased blood flow to the regions of the brain responsible for movement or motor activities would be associated with more fatigue in ME/CFS. Because some research indicates that the motor system might be left “on” in ME/CFS during the recovery period, perhaps reduced blood flow could ameliorate that (?).

In response to a question, Staud said the brain areas he found that make a difference in ME/CFS highly correlated with those that Dr. Hyde asserts are most relevant. The difficulty in accessing the brain makes it a problematic feature to change, but transcranial magnetic stimulation (TMS) is having some success redirecting the flows from one part of the brain to another. If the connectivity between different regions in the brain is indeed a major problem, it’s possible TMS could be helpful.